Sphingomyelin, a cell membrane component, can be hydrolyzed to ceramide and phosphorylcholine by acid or neutral sphingomyelinase (1,2). This hydrolysis event initiates an intracellular signalling cascade associated with the stimulation of numerous biological activities, including induction of apoptosis (3-10) and arrest of cell growth in the G0-G1 phase (11-13).
Sphingolipids have been shown to be biologically active and have numerous regulatory effects on cell function including cell growth and differentiation. A number of inducers of sphingomyelin hydrolysis causing concommitant elevation of intracellular ceramide have been identified. These include TNFα, endotoxins, interferon α, IL-1, Fas ligand, CD28, chemotherapeutic agents, heat and ionizing radiation (14, 15). The kinetics of endogenous ceramide formation and accumulation appear to be complex and variable in different cell systems and with different inducers of sphingomyelin catabolism (16-19). It has recently been established that endogenously generated ceramide acts as a second messenger and induces apoptosis (20). Ceramide synthesis de novo has been implicated in lethal responses to several chemotherapeutic agents such as anthracyclines (21) and ara-C (22). Many recent studies have examined the effect of exogenous ceramide on the induction of apoptosis in a variety of tumor cells. Ceramide has been shown in such cases to cause cell cycle arrest in several cell lines as well as apoptosis, cell senescence and terminal differentiation (23-26). Exogenous addition of ceramide has been shown to cause apoptosis in a variety of tumor cell lines (23, 30).
Ceramide (C6-ceramide) is an analog of endogenous ceramides, which are a major signaling pathway for apoptosis in cells undergoing stress or exposure to chemotherapy.